Over 1.4 billion people across the globe are affected by Neglected Tropical Diseases (NTD)—a group of thirteen parasitic and bacterial infections. NTD include the soil-transmitted helminthiasis, schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma, as well as trypanosomiasis and leishmaniasis. Often, individuals are infected with multiple NTD agents simultaneously. Currently, the effectiveness of all agents used to treat parasites is diminished by four factors: (a) resistance develops and spreads rapidly, (b) parasites do not actively transport drugs into their bodies, (c) many drugs (eg: anthelminthics) are effective only during certain developmental stages of the parasite, and (d) drugs tend to act on a specific type of parasite and are ineffective in controlling other parasite populations.
Although these are devastating diseases of global concern, their neglected status relative to other health concerns has resulted in a limited arsenal of therapeutic compounds for their treatment [Chatelain E, et al. Drug Des Devel Ther 2011, 5:175-181]. The trypanosomatid parasites L. major and L. amazonensis are causative agents of human cutaneous leishmaniasis in the Old World and New World, respectively. Combined, these two species are responsible for an estimated 2 million new infections annually with ˜350 million people living in areas of active parasite transmission. In many regions of the world, treatment of leishmaniasis still relies on toxic drugs such as pentavalent antimony, which requires high doses and lengthy courses of treatment, and alternative drugs are still costly and not widely available in endemic areas. This situation, combined with the recent increase in Leishmania infections in urban areas, highlights the urgent need for identification of essential pathways in these organisms that can be targeted by new drugs with lower toxicity.
It was previously demonstrated that the free-living roundworm C. elegans and parasitic nematodes cannot synthesize heme, an iron-containing heterocyclic organic ring structure, but instead acquires heme from either their environment or their host to survive and reproduce PMID: 15767563. It is generally accepted that parasites exhibit distinct adaptations that allow them to acquire nutrients unidirectionally from the host to sustain their growth and reproduction. An example of such an adaptation would be the uptake of heme which the parasite cannot produce but is synthesized by all vertebrates (hosts) via a highly conserved multi-step pathway [Hamza I, et al. Biochim Biophys Acta 2012, 1823(9):1617-1632]. This unusual requirement for external heme is also found in single-celled parasites such as Trypanosomes and Leishmania [Hamza I, et al. Biochim Biophys Acta 2012, 1823(9):1617-1632; Chang C S, et al. Mol Biochem Parasitol 1985, 16(3):267-276]. Thus, drugs that target heme transport pathways unique to the parasite and not shared by its mammalian host offers great therapeutic potential. A drug that blocks heme transport or that enters the parasite via a high affinity and essential heme uptake pathway can be a highly effective broad-spectrum therapeutic agent, since such transport mechanisms are likely to have similarities across multiple parasite species. Parasites that limit transport or become resistant to the drug will indirectly also limit heme uptake, suffering impaired growth and development, and this approach could be applied to the treatment of infections caused by a diverse group of parasites, including intestinal nematodes, lymphatic and cutaneous filarial nematodes, and the kinetoplastids Leishmania and Trypanosoma. Thus, there is an ongoing and unmet need for compounds that selectively inhibit targets that are exclusively expressed by the parasites, as opposed to their hosts, and for methods of using such compounds to limit growth or kill such parasites. The present disclosure meets this need.